Immunological Reprogramming by Radiation Therapy: Implications for Precision Cancer Treatment

ABSTRACT Radiation therapy (RT) is a main part of cancer treatment and is known mostly for its ability to directly kill cancer cells. However, recent studies have shown that RT can have potent immunomodulatory properties, which include both the ability to re‐program the tumour microenvironment (TME) and the activation of systemic anti‐tumour immune responses. It reviews the immune mechanisms involved in the killing of tumours after irradiation, such as immunogenic cell death (ICD), activation of the cGAS–STING (cyclic GMP–AMP synthase–stimulator of interferon genes) pathway, dendritic cell (DC) maturation, priming of cytotoxic T lymphocytes (CTLs), and the abscopal effect, which refers to the regression of non‐irradiated tumours following local irradiation. We also discuss how RT induces immunosuppressive counterforces such as regulatory T cells (Tregs), myeloid‐derived suppressor cells (MDSCs), and programmed death‐ligand 1 (PD‐L1) upregulation. The synergy between RT and immune checkpoint inhibitors (ICIs) such as anti‐programmed cell death protein 1 (anti‐PD‐1), anti‐programmed death‐ligand 1 (anti‐PD‐L1), and anti‐cytotoxic T‐lymphocyte‐associated protein 4 (anti‐CTLA‐4) agents is critically assessed. We also discuss possible clinically relevant enhancement of side effects of immunotherapies by RT. The induction of neo‐antigens and immune activation by chemotherapy (ChX) versus RT is compared/contrasted. Particular focus is paid to dose fractionation approaches, such as stereotactic body radiation therapy (SBRT) and stereotactic radiosurgery (SRS), and their differential immunogenic effects. The different tumour types that are most susceptible to radiotherapy‐induced immunologic responses are covered in great detail, particularly malignant melanoma. The field is contextualised with relevant clinical trials, emerging patents, and translational case studies. In this review, we seek to give an integrative framework for how radiation‐induced immune reprogramming can be harnessed in the design of next‐generation precision oncology strategies.